5-phenyl-1-sulfonamidopyrrole-2-propionic acids and congeners

ABSTRACT

Disclosed herein are anti-ulcerogenic, pepsin-inhibiting, antibacterial, and anti-protozoal 5-phenyl-1-sulfonamidopyrrole-2propionic acids and congeners; analgesic, anti-ulcerogenic, and anti-protozoal 2,3,4,5-tetra-hydro-3-hydroxy-6-phenyl-2sulfonylpyridazine-3-propionic acid gamma -lactones and congeners; and the preparation of these compounds from corresponding 4,7-dioxoheptanoic acids and sulfonic acid hydrazides.

United States Patent Sprenger [451 Sept. 19, 1972 [72] Inventor: WilliamK. Sprenger, Niles, ill.

[73] Assignee: G. l Searle & Co., Chicago, ll].

, [22] Filed: July 8, 1970 [21] Appl. No.: 53,335

[52] US. Cl ..260/326.3, 260/250 A, 424/274 [51] Int. Cl. ..C07d 27/26[58] Field of Search ..260/326.3

[56] References Cited UNITED STATES PATENTS 3,542,788 11/1970 Chinnetal. ..260/294 Primary Examiner-Alex Maze] Assistant Examiner-Joseph A.Narcavage Attorney-John M. Brown, John J. Kolano, Elliot N. Schubert,Lowell C. Bergstedt, Sybil Meloy, Walter C. Ramm and Helmuth A. Wegner[57] ABSTRACT Disclosed herein are anti-ulcerogenic, pepsin-inhibiting,anti-bacterial, and anti-protozoa]S-phenyl-l-sulfonamidopyrrole-Z-propionic acids and congeners;analgesic, anti-ulcerogenic, and anti-protozoal 2,3,4,5-tetra-hydro-3-hydroxy-6-phenyl-2-sulfonylpyridazine- 3-propionic acidy-lactones and congeners; and the preparation of these compounds fromcorresponding 4,7 -diox'oheptano ic acids and sulfonic acid hydrazides.

21 Claims, No Drawings NHSOQZ l N Pit-W 011201120 o R wherein Phrepresents phenyl optionally substituted by lower alkyl, lower alkoxy,and/or halogen; 2 represents lower alkyl or phenyl, the latteroptionally substituted by lower alkyl, lower alkoxy, halogen, and/ornitro; and R represents hydrogen or lower alkyl. From 1 to as many as ofthe aforesaid optional substituents, alike or different, can be present;and their positioning about the involved benzene rings is not critical.However, when Ph represents phenyl optionally substituted by loweralkyl, a single lower alkyl substituent is preferred, especially methyl;when Ph represents phenyl optionally substituted by lower alkoxy, fewerthan 3 lower alkoxy substituents are preferred; and when Ph representsphenyl optionally substituted by halogen, a single halogen substituentis preferred, especially halogen of atomic number less than 53 (i.e.,fluorine, chlorine, or bromine) and sometimes less than 35 (i.e.,fluorine or chlorine). Further, when Z represents phenyl substituted bylower alkyl, lower alkoxy, or nitro, a single such substituent ispreferred, particularly methyl if the substituent be lower alkyl;whereas when Z represents phenyl substituted by halogen, fewer than 4halogens are preferred, especially halogens of atomic number less than53.

The lower alkyls comprehended by Ph, Z, and R are typically methyl,ethyl, propyl, isopropyl, butyl, iso-butyl, see-butyl, tert.-butyl,pentyl, neopentyl, hexyl, isohexyl, heptyl, and like monovalent,saturated, acyclic, straightor branched-chain, hydrocarbon groupings ofthe formula wherein n represents a positive integer less than 8. Thelower alkoxys comprehended by Ph and Z are defined by the expressionO-lower alkyl wherein lower alkyl has the meaning assigned above; andthe halogens comprehended are, of course, fluorine, chlorine, bromine,and iodine.

The compounds to which this invention relates are useful by reason oftheir valuable biological properties. Thus, for example, they arepepsin-inhibiting, anti-ulcerogenic, anti-bacterial, and anti-protozoal.

The pepsin-inhibiting and anti-ulcerogenic utility of the instantcompounds is evident from the results of standardized tests carried outas described in U.S. Pat. No. 3,475,420 and US. Pat. No. 3,483,192,respectively. The anti-bacterial and anti-protozoal utility of theinstant compounds is evident from the results of standardized tests fortheir capacity to prevent the growth of Diplococcus pneumoniae andTetrahymena gelleii, respectively, carried out as also described in thelatter patent.

Further evidence of the anti-bacterial utility of the instant compoundsis provided by the results of a standardized test for their capacity toprevent the growth of Erwinia sp. In this test, nutrient broth(manufactured by Baltimore Biological Laboratories or Difco) is preparedat twice the concentration recommended by the manufacturer, sterilized,and inoculated with 2 percent (by volume) of a culture of Erwinia sp.Meanwhile, compound is heated in sterile distilled water at aconcentration of 2000 7 per ml. and a temperature of C. for 20 min. Anequivolume mixture of this compound preparation and the inoculated brothis incubated aerobically at 37 C. for 24-48 hr. and then examinedgrossly for growth of the test organism. If such growth is observed, thecompound is considered inactive. If no growth is observed, the incubatedmixture is serially diluted and mixed with an inoculated broth of thesame composition as before excepting that the concentration is halvedand 1 percent (by volume) of the culture instead of 2 percent isincorporated. Amounts of the latter broth is added such thatconcentrations of 100, 10, and l 'y of compound per ml. result. Themixtures thus obtained are incubated as before and then examined grosslyfor growth of the test organism. Potency is expressed as the minimumconcentration at which no growth of test organism is discernible.Controls are provided by concurrent incubations identical with theforegoing except for the absence of compound.

Further evidence of the anti-protozoa] utility of the instant compoundsis provided by the results of a standardized test for their capacity toimmobilize Tetrahymena pyriformis. In this test, a nutrient brothconsisting of 12 gm. of proteose peptone, 8 gm. of sucrose, and 500 ml.of water is sterilized and inoculated with 10 percent (by volume) of anaxenic culture of T. pyriformis. Meanwhile, compound is heated insterile distilled water at a concentration of 2000 7 per ml. and atemperature of 80 C. for 20 min. An equivolume mixture of this compoundpreparation and the inoculated medium is incubated aerobically at 32 C.for 48 hr. and then examined microscopically for the presence of motiletetrahymena. If any are observed, the compound is considered inactive.If no motile tetrahymena are observed, the incubated mixture is seriallydiluted and mixed with an inoculated medium of the same composition asthat described above excepting that 1000 parts of distilled waterinstead of 500 parts, and 5 percent (by volume) of the culture insteadof 10 percent, are incorporated. Amounts of the latter medium added aresuch that concentrations of 100, 10, and l 'y of compound per ml.result. The mixtures thus obtained are incubated as before and thenexamined microscopically for motile tetrahymena. Potency is expressed asthe minimum concentration at which no motile tetrahymena arediscernible. Controls are provided by concurrent incubations identicalwith the foregoing except for the absence of compound.

Those skilled in the art will recognize that observations of activity instandardized tests for particular biological effects are fundamental tothe development of valuable new drugs, both veterinary and human.

Preparation of the subject compounds proceeds by heating a4,7-dioxoheptanoic acid of the formula PhCOCH CH- COCH CH COOH with asulfonic acid hydrizide of the formula [Ph and Z being defined asbefore], using benzene as the reaction medium and p-toluenesulfonic acidmonohydrate as a condensing agent. The resultantlsulfonamidopyrrole-2-propionic acids are isolated by stripping thesolvent from the reaction mixture, extracting the residue with aqueoussodium bicarbonate, adding excess hydrochloric acid to the extract, andfiltering. The acids are esterified by heating with an alcohol of theformula lower alkyl-OH in the presence of sulfuric acid.

By-products of the reaction between the aforesaid 4,7-dioxoheptanoicacids and sulfonic acid hydrazides, insoluble in bicarbonate and soisolated from the reaction mixture, are2,3,4,5-tetrahydro-3-hdroxy-6-phenyl-2-sul-fonylpyridazine-Zi-propionicacid 'y-lactones and congeners of the formula Ph N-SOr-Z [Ph and 2 beingdefined as before] useful by reason of their valuable analgesic,anti-ulcerogenic, and antiprotozoal properties. They lack thepepsin-inhibiting utility of the compounds hereinafter claimed.

The anti-ulcerogenic utility of the instant lactones and theiranti-protozoal utility in respect of T. pyriformis, are evidenced fromthe results of the standardized tests described above, whereas theanalgesic utility of these lactones is evident from the results of astandardized test for their capacity to prolong the reaction time ofmice to a clip applied to the tail. The procedure is essentially that ofHaffner, Dtsch. med. Wschr., 55, 731 (1929), as described by Bianchi andFranceschini, Brit. J. PharmacoL, 9, 280 (1954), modified in certainparticulars as follows: A pressure-standardized artery clip is placed 1inch from the base of the tail of each of a group of adult, male,albino, Charles River mice weighing 18-25 gm.; and animals are selectedtherefrom which respond to the clip by turning, biting, or the likewithin sec. The response times for these 10 animals are recorded, theclips are removed, and 50 mg. per kg. of test compound is thereupon administered to each animal via intraperitoneal injection. Solid compoundsare prepared for injection by mixing 25 mg. with approximately 0.2 ml.of a 50:50 (by volume) mixture of propylene glycol and Tween 80, thendiluting to 5 ml. with water and homogenizing; liquid compounds areprepared by warming 25 mg. with 1 ml. of 50:50 (by volume) propyleneglycol and Tween 80, then diluting to 5 ml. with aqueous 10 percent gumacacia. At 30-min. intervals during the 2 hr. immediately followingadministration, the clips are replaced on the tails for a maximum of 30sec. in each instance, during which response times are recorded asbefore. If, at one or more intervals, response times for at least halfof the animals are more than twice as long as prior to compoundadministration, the compound is considered to be analgesic.

The following examples describe in detail compounds illustrative of thepresent invention, methods which have been devised for theirpreparation, and byproducts thereof. It will be apparent to thoseskilled in the art that many modifications, both of materials and ofmethods, may be practiced without departing from the purpose and intentof this disclosure. Throughout the examples hereinafter set forth,temperatures are given in degrees centigrade and relative amounts ofmaterials in parts by weight, except as otherwise noted.

EXAMPLE 1 2,3,4,5-Tetrahydro-3-hydroxy-2-methylsulfonyl-6-phenylpyridazine-3-propionic acid 'y-lactone and 1-methane-sulfonamido-S-phenylpyrrole-2-propionic acid. A mixture of 94parts of 4,7-dioxo-7-phenylheptanoic acid, 44 parts of methanesulfonicacid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 3600parts of benzene is heated at the boiling point under reflux for 2 hrs.,water being removed as formed. Solvent is stripped by vacuumdistillation, whereupon the residue is extracted with approximately 2000parts of warm aqueous 5 percent sodium bicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot methanol.The methanol solution is mixed with decolorizing charcoal and thenfiltered. From the filtrate, on cooling, colorless plates of2,3,4,S-tetrahydro-3-hydroxy-2-methylsulfonyl-6-phenylpyridazine-3-propionic acid -y-lactone crystallizes. Isolated byfiltration and dried in vacuo at 6065 it melts at 17 ll 73. It has theformula The bicarbonate extract is acidified with 10 percenthydrochloric acid, and the mixture which eventuates is extracted withether. The ether extract is washed with water, dried over magnesiumsulfate, and stripped of solvent by vacuum distillation. The residue istaken up in a minimum of hot aqueous methanol. The resultant solution ismixed with decolorizing charcoal and then filtered. From the filtrate,on cooling, cream-coloredlmethanesulfonamido-S-phenylpyrrole-2-propionic acid crystallizes.Isolated by filtration and dried in vacuo at 60-65, it melts at 187189.It has the formula NHSO2CH:

QKIOMHMOH EXAMPLE 2 NHSOgCH:

I N @W Wcmomcoocm EXAMPLE 32-Butylsulfonyl-2,3,4,5-tetrahydro3-hydroxy-6-phenylpyridazine-3-propionic acid 'y-lactone andl-butane-sulfonamido-5-phenylpyrrole-2-propionic acid. A mixture of 94parts of 4,7-dioxo-7-phenylheptanoic acid, 60 parts of butanesulfonicacid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 3600parts of benzene is heated at the boiling point under reflux for 3hours, water being removed as formed. Solvent is stripped by vacuumdistillation, whereupon the residue is extracted with approximately2,000 parts of warm aqueous 5 percent sodium bicarbonate.

The bicarbonate-insoluble material is2-butyl-sulfonyl-Z,3-4-5-tetrahydro-3-hydroxy-6-phenylpyridazine-3-propionic acid 'y-lactone, having the formula The bicarbonate extractis acidified with 10 percent hydrochloric acid, and the resultantmixture is extracted with ether. The ether extract is washed with water,dried over magnesium sulfate, and stripped of solvent by vacuumdistillation. The residue isl-butanesulfonamido-S-phenylpyrrole-2-propionic acid, having the formulaQTLTOMHMOH EXAMPLE 4 2,3,4,5-Tetrahydro-3-hydroxy-2-methylsulfonyl-6-(p-tolyl)pyridazine-3-propionic acid y-lactone and 1-methanesulfonamido-S-(p-tolyl)pyrrole-Z-propionic acid. Substitution ofparts of 4,7-dioxo-7-(ptolyl)heptanoic acid and 44 parts ofmethanesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acidand butanesulfonic acid hydrazide, respectively, called for in Example 3affords, by the procedure there detailed,2,3,4,S-tetrahydro-3-hydroxy-2-methylsulfonyl-6-(p-tolyl)pyridazine-3-propionicacid y-lactone, having the formula N N-soiom andl-methanesulfonamido-5-(p-tolyi)pyrrole-2- propionic acid, having theformula NHSOzCHa EXAMPLE 56-(p-Flu'orophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-methylsulfonylpyridazine-3-propionic acid 'y-lactone and5-(p-fluorophenyl)- l -methanesulfonamidopyrrole- 2-propionic acid. Amixture of 200 parts of 7-(pfluorophenyl)-4,7-dioxoheptanoic acid, 88parts of methanesulfonic acid hydrazide, 1 part of p-toluenesulfonicacid monohydrate, and 10,800 parts of benzene is heated at the boilingpoint under reflux for 1% hours, water being removed as formed. Solventis stripped by vacuum distillation, whereupon the resudue is extractedwith approximately 4,000 parts of warm aq ueous 5 percent sodiumbicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropylalcohol. The alcohol solu-' tion is mixed with decolorizing charcoal andthen filtered. From the filtrate, on cooling,o-(p-fluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-methylsulfonylpyridazine-S-propionic acid 'y-lactonecrystallizes. Isolated by filtration and dried in vacuo at 60-65, itmelts at approximately l53-1 5 4. It has the formula The bicarbonateextract is acidified with 10 percent hydrochloric acid, and the mixturewhich eventuates is extracted with ether. The ether extract is washedwith water, dried over magnesium sulfate, and stripped of solvent byvacuum distillation. The residue is taken up in a minimum of hot aqueousmethanol. The resultant solution is mixed with decolorizing charcoal andthen filtered. From the filtrate, on cooling, S-(p-fluorophen- /N F-Ucmomcoon EXAMPLE 62-Butylsulfonyl-6-(p-chlorophenyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionicacid -y-lactone and l-butanesulfonamido-5-(p-chlorophenyl)pyrrole-2-propionic acid. A mixture of 108 parts of7-(pchlorophenyl)-4,7-dioxoheptanoic acid, 62 parts of butanesulfonicacid hydrazide, 1 part of p-toluenesulfonic acid monohydrate, and 4,500parts of benzene is heated at the boiling point under reflux for 2hours, water being removed as formed. Solvent is stripped by vacuumdistillation, whereupon the residue is extracted with approximately2,000 parts of warm aqueous 5 percent sodium bicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropylalcohol. The alcohol solution is mixed with decolorizing charcoal andthen filtered. From the filtrate, on cooling, 2-butylsulfonyl-6-(p-chlorophenyl)-2,3,4,5-tetrahydro-3-hydr0xypyridazine-B-propionic acid'y-lactone crystallizes. Isolated by filtration and dried in vacuo at60-65, it

melts at approximately l58-l 59. It has the formula N QT n-sogclm Thebicarbonate extract is acidified with 10 percent hydrochloric acid, andthe mixture which eventuates is extracted with ether. The ether extractis washed with water, dried over magnesium sulfate, and stripped ofsolvent by vacuum distillation. The residue is taken up in a minimum ofhot aqueous methanol. The resultant solution is mixed with decolorizingcharcoal and then filtered. From the filtrate, on cooling,l-butanesulfonamido-S-(p-chlorophenyl)pyrrole-2-propionic acidcrystallizes. Isolated by filtration and dried in vacuo at 6065, itmelts at 228-230. It has the formula EXAMPLE 76-(m-Bromophenyl)-2-butylsulfonyl-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionicacid y-lactone and l-butanesulfamido-5-(m-bromophenyl)pyrrole-2-propionic acid. Substitution of 124 parts of7-(mbromophenyl-4,7-dioxoheptanoic acid for the 4,7-dioxo-7-phenylheptanoic acid called for in Example 3 and doubling theamounts of benzene and aqueous bicarbonate prescribed therein affords,by the procedure there detailed,6-(m-bromophenyl)-2-butylsulfonyl-2,3,4,S-tetrahydro-3-hydroxypyridazine-3-propionic acid y-lactone, of the formula N QT N-so2c.u,

l r I 0 and l-butanesulfonamido-5-(m-bromophenyl )pyrrole- 2-propionicacid, of the formula NIISOgCqII 111 QT Tanzania 0 OH Il 3r EXAMPLE 8 andl-butanesulfonamido-5-(p-iodophenyl)pyrrole-2- propionic acid, of theformula N 1- I l CIIQCIIzCOOII EXAMPLE 9 and p-methoxyphenyl l-methanesulfonamidopyrrole-2-propionic acid melting at approximately 19l-l92, of the formula IIIHSOQCHQ HBCOQW TOHZCHKJOOH EXAMPLE l06-(m-Ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-methylsulfonylpyridazine-3-propionic acid 'y-lactone and5-(m-ethoxyphenyl)- l -methanesulfonamidopyrrole-2-propionic acid.Substitution of 112 parts of 7- (m-ethoxyphenyl)-4,7-dioxoheptanoic acidand 44 parts of methanesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydraziderespectively, called for in Example 3 and increasing the amount ofbenzene prescribed therein from 3,600 to 5,400 parts affords, by theprocedure there detailed, 6-( m-ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-methylsulfonylpyridazine-3-propionic acid -y-lactone of theformula and 5(m-ethoxyphenyl)- l -methanesulfonamidopyrrole-2-propionicacid, of the formula NHSO CHa N QT cmcmcoon I I if EXAMPLE 1 l2-Butylsulfonyl-2,3,4,5-tetrahydro-3-hydroxy-6-( pmethoxyphenyl)pydazine-3-propionic acid y-lactone 5 andl-butanesulfonamido-5-(p-methoxyphenyl)pyrrole-2-propionic acid.Substitution of 106 parts of 7-(pmethoxyphenyl)-4,7-dioxoheptanoic acidfor the 7-(pchlorophenyl)-4,7-dioxoheptanoic acid called for in Example6 and increasing the amount of benzene prescribed therein from 4,500 to5,400 parts afiords, by the procedure there detailed, 2-butyl-sulfonyl-2,3,4,5-tetrahydro-3-hydroxy-6-(p-methoxyphenyl)pyridazine-3-propionicacid y-lactone melting at approximately 1 l0-l 1 1, of the formula andl-butanesulfonamido-5-(p-methoxyphenyl)pyr- 2 role-2propionic acidmelting at approximately l69-l7 0, of the formula EXAMPLE 126-(p-Chlorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-phenylsulfonylpyridazine-3-propionic acid 'y-lactone andl-benzenesulfonamido-S-(p-chlorophenyl)pyrrole- 2-pr0pionic acid.Substitution of 70 parts of benzenesulfonic acid hydrazide for thebutanesulfonic acid hydrazide called for in Example 6 and decreasing theamount of benzene prescribed therein from 4,500 to 3,600 parts affords,by the procedure there detailed,6-(p-chlorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-phenylsulfonylpyridazine-3-propionic acid y-lactone melting atapproximately 1 75-l 76, of the formula andl-benzenesulfonamido-5(p-chlorophenyl)pyrrole- 2-propionic acid meltingat approximately l94-l95, of the formula WQ N (lb-QT Tcmcmcoon EXAMPLEl3 6-(o-Fluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-phenylsufonylpyridazine-3-propionic acid -y-lactone andl-benzenesulfonamido-5-( o-fluorophenyl )pyrrole- 2-propionic acid.Substitution of 102 parts of 7-(0- fluorophenyl)-4,7-dioxoheptanoic acidand 70 parts of benzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide, respectively,called for in Example 3 and increasing the amount of benzene prescribedtherein from 3,600 to 4,500 parts affords, by the procedure theredetailed, 6-(o-fluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-Z-phenylsulfonylpyridzaine-3-propionic acid 7-lactone, of theformula and l-benzenesulfonamido-5-(o-fluorophenyl)pyrrole- 2-propionicacid, of the formula EXAMPLE l4 andl-benzenesulfonamido-5-(p-methoxyphenyl)pyrrole-2-propionic acid meltingat approximately l54-l 55, of the formula NHSO2- mo O-Q W u-cmcmc OOHEXAMPLE l5 Methyll-benzenesulfonamido-5-(p-methoxyphenyl)-pyrrole-2-propionate. A mixtureof 60 parts of lbenzene-sulfonamido-S-(p-methoxyphenyl)pyrrole-Z-propionic acid, approximately 2 parts of concentrated sulfuric acid, and1,600 parts of methanol is heated at the boiling point under reflux for5 hours, then diluted with one-half volume of water. Decolorizingcharcoal is added and the resultant mixture is rapidly heated to theboiling point and filtered hot. From the filtrate, on chilling to around5, colorless needles of methyl 1-benzenesulfonamido-S-(p-methoxyphenyl)pyrrole-2 propionate crystallize.Isolated by filtration and dried in vacuo at 6065, the product melts at12ll23. It

has the formula N moo-Q1 m-CIDCILC 00 0111 EXAMPLE l66-(m-Ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-phenylsulfonylpyridazine-3-propionic acid y-lactone andl-benzenesulfonamido-5-(m-ethoxyphenyDpyrrole-2-propionic acid.Substitution of 112 parts of 7- (m-ethoxyphenyl)-4,7-dioxoheptanoic acidand parts of benzenesulfonic acid hydrazide for the 4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide,respectively, called for in Example 3, and increasing the amount ofbenzene prescribed therein from 3,600 to 4,500 parts affords, by theprocedure there detailed, 6-( m-ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-phenylsulfonylpyridazine-3-pr0pionic acid 'y-lactone, of theformula and l-benzenesulfonamido-5-( m-ethoxyphenyl)pyrrole-2-propionicacid, of the formula F Q N GK Tcmomcoon EXAMPLE l76-(p-Fluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-(p-tolylsulfonyl)pyridazine-3-propionic acid y-lactone andS-(p-fluorophenyl l -(p-toluenesulfonamido)pyrrole-2-propionic acid. Amixture of parts of 7-(pfluoro-phenyl)-4,7-dioxoheptanoic acid, 74 partsof ptoluenesulfonic acid hydrazide, 1 part of p-toluenesulfonic acidmonohydrate, and 4,500 parts of benzene is heated at the boiling pointunder reflux for 2 hours, water being removed as formed. Solvent isstripped by vacuum distillation, whereupon the residue is extracted withapproximately 2,000 parts of warm aqueous percent sodium bicarbonate.

The bicarbonate-insoluble material is 6-( pfluorophenyl)-2,3,4,5-tetrahydro-3-hydroxy-2-(p-tolylsulfonyl)pyridazine-3-propionic acid 'y-lactone, of the formulaThe bicarbonate extract is acidified with percent hydrochloric acid, andthe mixture which eventuates is extracted with ether. The ether extractis washed with water, dried over magnesium sulfate, and stripped ofsolvent by vacuum distillation. The residue isS-(pfluorophenyl)-l-(p-toluenesulfonamido)pyrrole-2- propionic acidmelting at approximately l85l86. It

has the formula I IHS og-c m N F- Teutonic 0 OH EXAMPLE 18 6-(m-Bromophenyl )-2,3 ,4,5-tetrahydro-3-hydroxy-2-(o-tolylsulfonyl)pyridazine-3-propionic acid y-lactone and 5-(m-bromophenyl l -(o-toluenesulfonamido)pyrrole-Z-propionic acid.Substitution of 126 parts of 7-(m-bromo-phenyl) 4,7-dioxoheptanoic acidand 74 parts of o-toluenesulfonic acid hydrazide for the4,7-dioxo-7-phenyl-heptanoic acid and butanesulfonic acid hydrazide,respectively, called for in Example 3 and increasing the amount ofbenzene prescribed from 3,600 to 5,400 parts affords, by the procedurethere detailed, 6-(m-bromophenyl)-2,3,4,5tetrahydro-3-hydroxy-2-(o-tolysulfonyl)pyridazine-3- propionic acid'y-lactone, of the formula and 5-( m-bromophenyl 1o-toluenesulfonamido)pyrrole-2-propionic acid, of the formulaIYIHSOr-Q-CH: N cmomo OOH I [U Br EXAMPLE l9 and5-(p-bromophenyl)-l-(p-chlorobenzylsulfonamido)pyrrole-2-propionic acidmelting at approxi, mately 209-2l0, of the formula N m- W TomomooorrEXAMPLE 20 6-(o-Fluorophenyl)-2-(p-fluorophenylsulfonyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionic acid 'y-lactone and1-(p-fluorobenzenesulfonamido)-5- (o-fluoro-phenyl)pyrrole-2-propionicacid. Substitution of 102 parts of 7-(ofluorophenyl)-4,7-dioxoheptanoicacid and parts of p-fluorobenzenesulfonic acid hydrazide for the4,7dioxo-7-phenyl-heptanoic acid and butanesulfonic acid hydrazide,respectively, called for in Example 3 and increasing the amount ofbenzene prescribed therein from 3,600 to 4,500 parts affords, by theprocedure there detailed, 6-(0-fluorophenyl)-2-(p-fluorophenylsulfonyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionic acid 7- lactone, of theformula and l-(p-fluorobenzenesulfonamido)5-(o-fluorophenyl)pyrrole-2-propionic acid, of the formula EXAMPLE 212,3,4,S-Tetrahydro-3-hydroxy-6-(p-iodophenyl)-2-(p-iodophenylsulfonyl)pyridazine-3-propionic acid 'ylactone andl-(p-iodobenzenesulfonamido)-5-(piodophenyl)pyrrole-2-propionic acid.Substitution of 72 parts of 7-(p-iodophenyl)-4,7-dioxoheptanoic acid and60 parts of p-iodobenzenesulfonic acid hydrazide for the4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide,respectively, called for in Example 3 affords, by the procedure theredetailed,2,3,4,5-tetrahydro-3-hydroxy-6(p-iodophenyl)-2-(piodophenylsulfonyl)pyridazine-3-propionicacid 'y-lactone, of the formulahydroxy-6-(p-methoxyphenyl)pyridazine-3-propionic acid 'y-lactone andl-(p-fiuorobenzenesulfonamido)-- (p-methoxy-phenyl)pyrrole-Z-propionicacid. A mixture of 126 parts of 7-(p-methoxyphenyl)-4,7-dioxoheptanoicacid, 90 parts of p-fluorobenzenesulfonic acid hydrazide, 1 part ofp-toluene-sulfonic acid monohydrate, and 4500 parts of benzene is heatedat the boiling point under reflux for 2 hours, water being removed asformed. Solvent is stripped by vacuum distillation, whereupon theresidue is extracted with approximately 2000 parts of warm aqueous 5percent sodium bicarbonate.

The bicarbonate-insoluble material is2-(pfluorophenylsulfonyl)-2,3,4,5-tetrahydro-3-hydroxy-6-(p-methoxyphenyl)pyridazine-B-propionic acid y-lactone, having theformula The bicarbonate extract is acidified with 10 percenthydrochloric acid, and the mixture which eventuates is extracted withether. The ether extract is washed with water, dried over magnesiumsulfate, and stripped of solvent by vacuum distillation. The resudue istaken up in a minimum of hot aqueous isopropyl alcohol. The resultantsolution is mixed with decolorizing charcoal and'then filtered. From thefiltrate, on cooling, l-(pl6fluorobenzenesulfonamido)-5-(p-methoxyphenyl)pyrrole-2-propionic acidcrystallizes. Isolated by filtration and dried in vacuo at 6065, itmelts at approximately 1 -l7 1. It has the formula N 1n o Teutonic 0 onEXAMPLE 23 2-(p-Bromophenylsulfonyl)-6-(m-ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionic acid y-lactone and1-(p-bromobenzenesulfonamido)-5- (m-ethoxy-phenyl)pyrrole-Z-propionicacid. Substitution of parts of 7-(m-ethoxyphenyl)-4,7-dioxoheptanoicacid and 126 parts of p-bromobenzenesulfonic acid hydrazide for the7-(p-chlorophenyl)-4,7-dioxoheptanoic acid and butanesulfonic acidhydrazide, respectively, called for in Example 6 and shortening thereaction time prescribed therein from 2 to 1% hours affords, by theprocedure there detailed,2-(pbromophenylsulfonyl)-6-(m-ethoxyphenyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionic acid 7- lactone melting atapproximately l69-l 70, of the formula andl-(p-bromobenzenesulfonamido)-5-( m-ethoxyphenyl)pyrrole-2-propionicacid melting at approximately l77l 78, of the formula EXAMPLE 24 2-(2,4,5-Trichlorophenylsulfonyl)-2,3 ,4,5-tetrahydro-3-hydroxy-6-(p-methoxyphenyDpyridazine- 3-propionic acid'y-lactone and l-( 2,4 ,5-trichlorobenzenesulfonamido)-5-(p-methoxyphenyl)pyrrole-2-propionicacid. A mixture of 106 parts of 7-(p-methoxyphenyl)-4,7-dioxoheptanoicacid, 110 parts of 2,4,5-trichlorobenzenesulfonic acid hydrazide, 1 partof p-toluenesulfonic acid monohydrate, and 4,500 parts of benzene isheated at the boiling point under reflux for 3 hours, water beingremoved as formed. Solvent is stripped by vacuum distillation, whereuponthe residue is extracted with approximately 2,000 parts of warm aqueous5 percent sodium bicarbonate.

The bicarbonate-insoluble material is 2-(2,4,5- trichlorophenylsulfonyl)-2,3 ,4,5tetrahydro-3-hydroxy-6-(p-methoxyphenyl)pyridazine-3-propionic acid 'ylactone, of theformula The bicarbonate extract is acidified with 10 percenthydrochloric acid, and the mixture which eventuates is 10 extracted withether. The ether extract is washed with water, dried over magnesiumsulfate, and stripped of solvent by vacuum distillation. The residue istaken up in a minimum of hot aqueous isopropyl alcohol. The resultantsolution is mixed with decolorizing charcoal and then filtered. From thefiltrate, on cooling, 1-(2,4,5-trichlorobenzenesulfonamido)--(p-methoxyphenyl)pyrrole-Z-propionicacid crystallizes. Isolated by filtration and dried in vacuo at 60-65,it melts at approximately 230-23 1. it has the formula2,3,4,5-Tetrahydro-3-hydroxy-6-(2,5-dimethoxyphenyl)-2-(p-methoxyphenylsulfonyl)pyridazine-3-propionic acid 'y-lactone and l(p-methoxybenzenesulfonamido)-5-(2,5-dimethoxyphenyl)pyrrole-3- propionicacid. A mixture of 160 parts of 7-(2,5-methoxyphenyl)-4,7-dioxoheptanoic acid [prepared from2,S-dimethoxyacetophenone and 2-fural-dehyde by the procedure describedin U.S. Pat. No. 3,349,091 (Example 1, parts A and B) for thepreparation of 7-(ofluorophenyl)4,7-dioxoheptanoic acid], 110 parts ofp-methoxybenzenesulfonic acid hydrazide, 1 part of ptoluene-sulfonicacid monohydrate, and 4,500 parts of benzene is heated at the boilingpoint under reflux for 1% hours, water being removed as formed. Solventis stripped by vacuum distillation, whereupon the residue is extractedwith approximately 2,000 parts of warm aqueous 5 percent sodiumbicarbonate.

Bicarbonate-insoluble material is taken up in a minimum of hot isopropylalcohol. The alcohol solution is mixed with decolorizing charcoal andthen filtered. From the filtrate, on cooling, 2,3,4,5-tetrahydro-3-hydroxy-6-(2,5-dimethoxyphenyl)-2-(p-methoxyphenylsulfony])pyridazine-3-propionicacid y-lactone crystallizes. Isolated by filtration and dried in vacuoat 6065, it melts at approximately 160-l 61. It has the formula HaCO Thebicarbonate extract is acidified with 10 percent hydrochloric acid, andthe mixture which eventuates is extracted with ether. The ether extractis washed with water, dried over magnesium sulfate, and stripped ofsolvent by vacuum distillation. The residue is taken up in a minimum ofhot aqueous isopropyl alcohol. The resultant solution is mixed withdecolorizing charcoal and then filtered. From the filtrate, on cooling,l(pmethoxybenzene-sulfonamido)-5-(2,5-dimethoxyphenyl)pyrroleZ-propionicacid crystallizes. Isolated by filtration and dried in vacuo at -65, itmelts at approximately l98-199. It has the formula N.lISOg-OCH3 EXAMPLE26 6-(m-Ethoxyphenyl)-2-(p-ethoxyphenylsulfonyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-3-propionic acid y-lactone andl-(p-ethoxybenzenesulfonamido)- S-(m-ethoxy-phenyl)pyrrole-2-propionicacid. Substitution of 112 parts of 7-(m-ethoxyphenyl)-4,7-dioxoheptanoicacid and 88 parts of p-ethoxybenzenesulfonic acid hydrazide for the4,7-dioxo-7-phenylheptanoic acid and butanesulfonic acid hydrazide,i'espectively, called for in Example 3 affords, by the procedure theredetailed 6-(m-ethoxyphenyl)-2-(pethoxyphenyl-sulfonyl)-2,3,4,5-tetrahydro-3-hydroxypyridazine-S-propionic acid 'y-lactone, ofthe formula and l-(p-ethoxybenzenesulfonamido)-5-(m-ethoxyphenyl)pyrrole-2-propionic acid, of the formula rwnsm-Gomm /NEXAMPLE 27 nyl)pyridazine-3-propionic acid 'y-lactone, of the formulaand 5-(p-bromophenyl)-l-(p-nitrobenzenesulfonamido)pyrrole-Z-propionicacid.

The latter product is heated for 2 hours at 90-95 with 2,300 parts ofmethanol containing approximately 4 parts of sulfuric acid. From theresultant mixture, on cooling, yellow methyl5-(p-bromo'phenyl)-l-(pnitrobenzenesulfonamido)-pyrrole-2-propionatecrystallizes. Isolated by filtration and dried in vacuo at 60-65, itmelts at 227-230. It has the formul ITTIIS02NOz N lat-Q {011201120 0 on:

EXAMPLE 28 i I O VC O and o-fluorophenyl 1 onitrobenzenesul fonamido)pyrrole-2-propionic acid, of the formula nsm- N [Wcmcmcoon What isclaimed is: 1. A compound of the formula N l n-H Tomcmo 0 on wherein Phrepresents phenyl optionally substituted by methyl, halogen, or fewerthan 3 lower alkoxys; R represents hydrogen or lower alkyl; and 2represents lower alkyl or phenyl optionally substituted by methyl, loweralkoxy, nitro, or fewer than four halogens.

2. A compound according to claim 1 having the formula I N Tomclncoonwherein R represent hydrogen or lower alkyl.

3. A compound according to claim 1 which islmethanesulfonamido-S-phenylpyrrole-2-propionic acid.

4. A compound according to claim 1 having the formula l N HTourer-1200011 5. A compound according to claim 1 which is5-(pfluorophenyl)-1-methanesulfonamidopyrrole-Z- propionic acid.

6. A compound according to claim 1 having the formula Lower alkox IIIH SO;1ower alkyl N H Temcmcoon l l nlogcn 7. A compound according to claim1 which is 5-(pmethoxyphenyl l -methanesulfonamidopyrrole-2- propionicacid. I

8. A compound according to claim 1 having the formula wherein X ishalogen of atomic number less than 35.

9. A compound according to claim 1 which islbenzenesulfonamido-S-(p-chlorophenyl)pyrrole-2- propionic acid.

10. A compound according to claim 1 having the formula Lower alkoxIIIHSO2 N @T TCIIEOHZCOOR wherein R represents hydrogen or lower alkyl.

11. A compound according to claim 1 which islbenzenesulfonamido-5-(p-methoxyphenyl)pyrrole-Z- propionic acid.

12. A compound according to claim 1 having the formula CH: 1TIIISO2wherein X represents halogen of atomic number less than 53.

13. A compound according to claim 1 which isS-(pfluorophenyl)-l-(p-toluenesulfonamido)pyrrole-2- propionic acid.

14. A compound according to claim 1 having the formula IIIH S Oe-Q-lmlugm N omcmcoon Halogen ,15. A compound according to claim 1 whichis -(pbromophenyl)-l-(p-chlorobenzenesulfonamido)pyrrole-2-propionicacid.

16. A compound according to claim I having the formula Lower alkoxybIIIISOZ Z wherein Z represents phenyl substituted by fewer than 4halogens of atomic number less than 53.

17. A compound according to claim 1 which isl-(pfluorobenzenesulfonamido )-5-(p-methoxyphenyl)pyrrole-2-propionicacid.

18. A compound according to cl: Am 1 having the formula N lll-u HClhQllaCOOll X IIHISO2 N For-nomooon wherein X represents halogen ofatomic number less than 53.

21. A compound according to claim 1 which is methyl 5-( p-bromophenyl lp-nitrobenzenesulfonamido)pyrrole-Zpropionate.

2. A compound according to claim 1 having the formula
 3. A compoundaccording to claim 1 which is1-methanesulfonamido-5-phenylpyrrole-2-propionic acid.
 4. A compoundaccording to claim 1 having the formula
 5. A compound according to claim1 which is 5-(p-fluorophenyl)-1-methanesulfonamidopyrrole-2-propionicacid.
 6. A compound according to claim 1 having the formula
 7. Acompound according to claim 1 which is5-(p-methoxyphenyl)-1-methanesulfonamidopyrrole-2-propionic acid.
 8. Acompound according to claim 1 having the formula
 9. A compound accordingto claim 1 which is1-benzenesulfonamido-5-(p-chlorophenyl)pyrrole-2-propionic acid.
 10. Acompound according to claim 1 having the formula
 11. A compoundaccording to claim 1 which is1-benzenesulfonamido-5-(p-methoxyphenyl)pyrrole-2-propionic acid.
 12. Acompound according to claim 1 having the formula
 13. A compoundaccording to claim 1 which is5-(p-fluorophenyl)-1-(p-toluenesulfonamido)pyrrole-2-propionic acid. 14.A compound according to claim 1 having the formula
 15. A compoundaccording to claim 1 which is5-(p-bromophenyl)-1-(p-chlorobenzenesulfonamido)pyrrole-2-propionicacid.
 16. A compound according to claim 1 having the formula
 17. Acompound according to claim 1 which is1-(p-fluorobenzenesulfonamido)-5-(p-methoxyphenyl)pyrrole-2-propionicacid.
 18. A compound according to claim 1 having the formula
 19. Acompound according to claim 1 which is1-(p-methoxybenzenesulfonamido)-5-(2,5-dimethoxyphenyl)-pyrrole-2-propionicacid.
 20. A compound according to claim 1 having the formula
 21. Acompound according to claim 1 which is methyl5-(p-bromophenyl)-1-(p-nitrobenzenesulfonamido)pyrrole-2propionate.